title: CD82 regulates STAT5/IL-10 and supports survival of acute myelogenous leukemia cells.
abstract: We recently reported that adhesion molecule CD82 is aberrantly expressed in CD34(+) /CD38(-) leukemia stem cells (LSCs). Here, we report the results of a functional analysis of CD82 in CD34(+) /CD38(-) acute myelogenous leukemia (AML) cells. Short hairpin (sh)RNA-mediated downregulation of CD82 resulted in a decrease in the level of IL-10. In contrast, forced expression of CD82 in CD34(+)/CD38(+) AML cells by transduction with CD82-expressing lentiviral particles resulted in an increase in the levels of IL-10. Notably, exposure of CD34(+)/CD38(-) AML cells to IL-10 stimulated clonogenic growth of these cells. Moreover, downregulation of CD82 by a shRNA dephosphorylated STAT5 in CD34(+)/CD38(-) AML cells. On the other hand, forced expression of CD82 resulted in increase in the levels of p-STAT5 in CD34(+)/CD38(+) AML cells. Chromatin immunoprecipitation (ChIP) assay results indicated that STAT5A binds to the promoter region of the IL-10 gene, while reporter gene assay results indicated stimulation of IL-10 expression at the transcriptional level. These results suggest that CD82 positively regulates the STAT5/IL-10 signaling pathway. Moreover, shRNA-mediated downregulation of CD82 expression in CD34(+)/CD38(-) AML cells dephosphorylated STAT5 in immunodeficient mice. Taken together, our data suggest that the CD82/STAT5/IL-10 signaling pathway is involved in the survival of CD34(+)/CD38(-) AML cells and may thus be a promising therapeutic target for eradication of AML LSCs.
authors.affiliation: Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan; Research Fellow of the Japanese Society for the Promotion of Science (JSPS), Chiyoda-ku, Tokyo, 102-8472, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Atsuya
authors.initials: A
authors.lastname: Nobumoto
authors.forename: Sayo
authors.initials: S
authors.lastname: Kataoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuda
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D051861:Kangai-1 Protein / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: C497688:CD82 protein, human; C508609:IL10 protein, human; D051861:Kangai-1 Protein; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D016753:Interleukin-10
keywords: AML; CD82; IL-10; STAT5; leukemia stem cells